Common sample zone noninvasive glucose concentration determination analyzer apparatus and method of use thereof

ABSTRACT

The invention comprises a method and apparatus for sampling a common tissue volume and/or a common skin layer skin of a person as a part of noninvasive analyte property determination system, comprising the steps of: providing an analyzer, comprising at least three detectors at least partially embedded in a probe housing, the probe housing comprising a sample side surface, the detectors including a first and second range of detection zones of differing radial distances from a first illumination zone and second illumination zone, respectively coupled to separate sources; repetitively illuminating the illumination zones of the skin with photons in a range of 1200 to 2500 nm; and detecting portions of light from the sources with the at least three detectors, the detectors positioned on a common line with the sources.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is:

-   -   a continuation-in-part of U.S. patent application Ser. No.         16/691,611 filed Nov. 22, 2019;     -   a continuation-in-part of U.S. patent application Ser. No.         16/691,615 filed Nov. 22, 2019; and     -   a continuation-in-part of U.S. patent application Ser. No.         15/829,877 filed Dec. 2, 2017, which is a continuation-in-part         of U.S. patent application Ser. No. 15/636,073 filed Jun. 28,         2017, which claims benefit of U.S. provisional patent         application no. 62/355,507 filed Jun. 28, 2016.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to noninvasively determining glucose concentration in a living body using an optical analyzer, such as a visible/near-infrared noninvasive glucose concentration determination analyzer.

Discussion of the Prior Art

There exists in the art a need for noninvasively determining glucose concentration in the human body.

SUMMARY OF THE INVENTION

The invention comprises a noninvasive glucose concentration analyzer apparatus and method of use thereof.

DESCRIPTION OF THE FIGURES

A more complete understanding of the present invention is derived by referring to the detailed description and claims when considered in connection with the Figures, wherein like reference numbers refer to similar items throughout the Figures.

FIG. 1 illustrates use of an applied force-optic analyzer;

FIG. 2 illustrates a noninvasive analyzer;

FIG. 3A illustrates an applied force system, FIG. 3B illustrates a transducer,

FIG. 3C illustrates transducer movement normal to an optical axis, FIG. 3D illustrates a z-axis transducer, and FIG. 3E illustrates a multi-axes off-center spinning mass transducer;

FIG. 4A illustrates spectrometer components, FIG. 4B illustrates an affixing layer, and FIG. 4C illustrates a coupling fluid enhanced affixer;

FIG. 5A illustrates a force system coupled to a spectrometer and FIG. 5B illustrates a force system embedded in a spectrometer;

FIG. 6 illustrates photons interacting with applied force wave(s) in tissue;

FIG. 7A illustrates absorbance of skin constituents, FIG. 7B illustrates fat and protein absorbance, FIG. 7C illustrates intensity as a function of depth/distance, and FIG. 7D illustrates scattering;

FIG. 8 illustrates detector selection;

FIG. 9 illustrates changing detector selection with tissue change;

FIG. 10A illustrates a transducer force applicator and FIG. 10B and FIG. 10C illustrate transducer force detectors in lines and arcs respectively;

FIG. 11A illustrates radial optical detection of force waves, FIG. 11B illustrates an array of optical detectors, and FIG. 11C illustrates arcs of optical detectors;

FIG. 12 illustrates optical probes observing tissue modified by force waves in a noninvasive glucose concentration determination system/analyzer;

FIG. 13 illustrates a multi-sensor analyzer system;

FIG. 14A illustrates spirally distributed detectors and FIG. 14B and FIG. 14C illustrate depth and radial distance resolution;

FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D illustrate depth selection from various angles in two separate units;

FIG. 16A, FIG. 16B, FIG. 16C, and FIG. 16D illustrate tissue sample position selection; and

FIG. 17 illustrates a common depth and common detector analyzer probe tip;

FIG. 18 illustrates a common depth and common sample position probe tip;

FIG. 19A and FIG. 19B illustrate a first and second tissue classification system, respectively;

FIG. 20A and FIG. 20B illustrate a multiplexed common zone sample system; and

FIG. 21 illustrates a common detector/common zone sample system.

Elements and steps in the figures are illustrated for simplicity and clarity and have not necessarily been rendered according to any particular sequence. For example, steps that are performed concurrently or in different order are illustrated in the figures to help improve understanding of embodiments of the present invention.

Problem

There remains in the art a need for a noninvasive glucose concentration analyzer.

DETAILED DESCRIPTION OF THE INVENTION

The invention comprises a method and apparatus for sampling a common tissue volume and/or a common skin layer skin of a person as a part of noninvasive analyte property determination system, comprising the steps of: providing an analyzer, comprising at least three detectors at least partially embedded in a probe housing, the probe housing comprising a sample side surface, the detectors including a first and second range detection zones of differing radial distances from a first illumination zone and second illumination zone, respectively coupled to separate sources; repetitively illuminating the illumination zones of the skin with photons in a range of 1200 to 2500 nm; and detecting portions of light from the sources with the at least three detectors, the detectors positioned on a common line with the sources.

Herein, generally, when describing an optical portion of the applied force-optic analyzer, a z-axis is aligned with a mean direction of the photons in a given sub-portion of the analyzer, such as along a longitudinal path of the photons into skin of a subject, and x- and y-axes form a plane perpendicular to the z-axis, such as at an interface point of incident photons into the skin of the subject. At the point of contact of the applied force-optic analyzer with the biological sample, the z-axis is normal/perpendicular to the sample and the x/y-plane tangentially contacts the sample. For instance, the light moves dominantly along the z-axis along vectors approaching perpendicular to an upper arm of a subject or a patient and the x/y-plane tangentially touches the upper arm along the z-axis. In particular cases, a second x,y,z-axis system is used to describe the sample itself, such as a z-axis being along the longitudinal length of a body part, such as along a digit or a finger or along the length of an arm section and the x/y-plane in this case is a cross-section plane of the body part.

A sample is optionally any material responding to an applied physical force in a manner observed by a probing optical system. However, for clarity of presentation and without loss of generality, the sample is described as a person, subject, patient, and/or a living tissue, such as skin and/or a portion of a human or animal. While the analyzer is described as a noninvasive analyzer probing into and optionally through the outer layers of skin, the noninvasive analyzer is optionally used as and or in conjunction with a minimally invasive glucose concentration analyzer and/or in conjunction with an invasive glucose concentration analyzer.

Herein, an illumination zone and/or an imaging zone is a point, region, or area of intersection of the illumination/imaging beam and/or pulse with an incident surface of the sample to yield a spectrum and/or an image of a desired volume of the sample. Herein, a detection zone is a point, region, or area of the sample sampled and/or visualized by one or more detectors. Similarly, herein an applied force zone is an incident point, region, or area of intersection at which an applied force is applied to the sample and a detected force zone is a point, region, or area of the sample interfacing with a force detector.

Applied Force-optic Analyzer

Referring now to FIG. 1, a noninvasive analysis system 100 using an analyzer 110, such as an applied force-optic analyzer system is illustrated. Generally, an optional force system 200 is used to apply one or more applied forces, physical distortions, and/or force waves to a sample 300. The applied force travels with a wave front, as a wave, in a pattern of compression and rarefication, and/or as a traveling displacement through the sample 300 or portions thereof. With or without application of the force waves, a spectrometer 140 is used to noninvasively collect spectra of the sample 300 and photometrically determine one or more properties of the sample, such as a glucose concentration. As described infra, the applied force is optionally in the form of an acoustic wave. However, the applied force is optionally and preferably a physical displacement of a portion of skin of a person, where the physical displacement is caused by movement of a mechanical object relative to the body to yield a time varying displacement of skin and/or constituents of the skin by the mechanical object. As described, infra, a variety of force provider technologies are available to variably displace the skin in a controlled manner. For clarity of presentation and without loss of generality, a transducer is used as an example to represent an applied force section of the force system 200, where a transducer comprises a device that receives a signal/force in the form of one type of energy and converts it to a signal/force in another form. Again for clarity of presentation and without loss of generality, a piezoelectric actuator is used to represent a transducer and an off-center spinning mass is used to represent a transducer. Hence, again for clarity of presentation and without loss of generality, a piezoelectric-optical analyzer or simply a piezo-optic analyzer, a transducer, and/or a transducer force applicator is used to describe any and all applied force electromechanical sources in the force system 200. Optionally, more than one transducer is used to yield displacement of the surface of the skin/skin, such as at a function of time and/or position.

Referring now to FIG. 2, use of the analyzer 110 is described. Generally, the analyzer 110 is optionally calibrated using a reference 310 and is used to measure a subject 320, where the subject 320 is an example of the sample 300. Optionally and preferably, the analyzer 110 and/or a constituent thereof communicates with a remote system 130 using a wireless communication protocol 112 and/or a wired communication protocol.

Force System

Referring now to FIGS. 3(A-E), the force system 200 is further described. Generally, the force system 200 comprises a force delivery transducer that directly and/or indirectly contacts the sample 300, such as an outer skin surface 330 of the subject 320 and/or a patient. The subject 320 has many skin layers 340, which are also referred to herein as tissue layers. For clarity of presentation, the skin layers 340 are represented as having a first skin layer, such as a stratum corneum 342; a second skin layer, such as an epidermis 344 or epidermal layer; a third skin layer, such as a dermis 346 or dermis layer; and a fourth layer, such as subcutaneous fat 348 or a subcutaneous fat layer. It is recognized that skin is a complex organ with many additional layers and many sub-layers of the named layers that vary in thickness and shape with time. However, for clarity of presentation and without loss of generality, the stratum corneum, epidermis, dermis, and subcutaneous fat layers are used to illustrate impact of the force delivery transducer on the skin layers 340 of the subject 320 and how the applied force waves alter optical paths of probing photons in the spectrometer 140 of the analyzer 110 in the noninvasive analysis system 100.

Still referring to FIG. 3A, at a first time, t₁, the tissue layers 340 are in a first state. As illustrated, the tissue layers 340 are in a compressed state 340, such as a result of mass of the force system 200 sitting on the skin surface 330, as a result of dehydration of the subject 320, and/or as a result of a physiological and/or environmental force on the tissue layers 340 of the subject. At a second time, t₂, the force system 200 applies a force wave 250 to the skin surface 330 of the patient 320, which sequentially propagates into the stratum corneum 342, epidermis 344, dermis 346, and given enough force into the subcutaneous fat 348. In additional to the force wave propagating into the skin layers 340 along the z-axis, the force wave propagates radially through the skin layers, such as along the x/y-plane of the skin layers. As illustrated at the second time, t₂, as the force wave 250 propagates into the tissue layers 340, the tissue layers expand and/or rarefy, such that the thickness of the epidermis 344 and/or the dermis 346 layers expands. The rarefication of the epidermis 344 and particularly the dermis 346 allows an increased and/or enhanced perfusion of blood 350 into the rarefied layers. The increased prefusion increases water concentration in the perfused layers, increase and/or changes distance between cells in the perfused layers, and/or changes shapes of cells in the perfused layers, such as through osmolarity induced changes in concentration in and/or around blood cells, such as red blood cells. Generally, scattering coefficients of the epidermis layer and/or especially the dermis layer changes, which is observed by the spectrometer 140 in the range of 400 to 2500 nm with larger changes at smaller wavelengths in the visible, 400 to 700 nm, and/or near-infrared, 700 to 2500 nm, regions. As illustrated at the third time, t₃, as the force wave 250 continues propagation in the tissue layers 340, the perfusion 350 continues to increase, such as to a maximum perfusion. As illustrated at the fourth time, t₄, after discontinuation of the force wave 250, the skin layers 340 revert toward the initial state of the non-force wave induced perfusion to a local minimum perfusion, which may match the initial perfusion, is likely higher than the initial perfusion, and is at times less than the initial perfusion due to changes in state of the environment, such as temperature, and/or generalized state of the subject 320, such as hydration, localized hydration of skin, such as due to food intake, insulin response to food intake, exercise level, blood pressure, and/or the like. Generally, the tissue layers 340 of the subject increase in thickness and/or rarefy during application of the transducer applied force wave 250 and decrease and/or compress after termination of the transducer applied force wave 250 to the skin surface 330 of the subject 320. The process of applying the force wave 250 is optionally and preferably repeated n times, where n is a positive integer of greater than 1, 2, 5, 10, 100, 1000, or 5000 times in a measurement period of an analyte of the subject 320, such as a glucose concentration. Generally, the cycle of applying the force wave 250 results in a compression-rarefication cycle of the tissue that alters an observed scattering and/or absorbance of probing photons in the visible and near-infrared regions. The force wave 250 is optionally and preferably applied as a single ping force in a tissue state classification step, as multiple pings in a tissue classification step, and/or as a series of waves during a tissue measurement step. Individual waves of a set of force waves are optionally controlled and varied in terms of one or more of: time of application, amplitude, period, frequency, and/or duty cycle.

Still referring to FIG. 3A and referring now to FIGS. 3(B-D), a force wave input element 210 of the force system 200 is illustrated. As illustrated, the force wave input element 210, such as a transducer 220, is equipped with one or of: a left transducer 221, a right transducer 222, a front transducer 223, a back transducer 224, a top transducer 225, and/or a bottom transducer 226. For instance, the left and/or right transducers 221, 222 move the force wave input element 210 left and/or right along the x-axis; the front and/or back transducers 223, 224 move the force wave input element 210 forward and/or back along the y-axis; and/or the top and bottom transducers 225, 226 move the force wave input element 210 up and/or down along the z-axis along and/or into the skin surface 330 of the subject 320, which moves the skin, skin layers 340, and/or skin surface 330 of the subject relative the spectrometer 140 and/or is a source of the force wave 250 moving, in the skin layers 340, along the z-axis into the skin, and/or radially outward from an interface zone of the force wave input element 210 of the force system 200. A transducer itself is optionally used as the force wave impulse element 210. Referring now to FIG. 3E, one or more off-center mass elements 230 is optionally spun or rotated, such as with an electric motor, along one or more of the x,y,z-axes to move the force wave input element 210 relative to the skin surface 330 of the subject 320 resulting movement of the skin of the subject 320 relative to the spectrometer 140 and/or cycling and/or periodic displacement of the tissue layers 340 of the subject 320 due to movement of the force wave input element 210 resulting in the force wave(s) 250. Generally, the force system 200 induces a movement of a sampled zone of skin of the subject 320, applies a displacement of a sampled zone of the skin of the subject 320, and/or applies a propagating force wave into and/or through a sample zone of tissue layers 340 of the subject, where the sampled zone is probed using photons from the spectrometer 140 and/or is measured using a set of detection zone transducers, described infra. The force wave(s) are optionally and preferably applied as a single input ping wave, a set of input ping waves, and/or are applied with a frequency of 0.01 Hz to 60 Hz. Optionally and preferably, the force waves 250 are applied with a frequency greater than 0.01, 0.02, 0.05, 0.1, or 1 Hz. Optionally and preferably, the force waves 250 are applied with a frequency of less than 200, 100, 50, 40, 30, or 20 Hz. Optionally and preferably, the force waves 250 are applied with a frequency within 5, 10, 25, 50, or 100 percent of 2, 4, 6, 8, 10, 12, 15, and 20 Hz.

Optical System

Referring now to FIG. 4A, the spectrometer 140 of the analyzer 110 is further described. The spectrometer 140 comprises a source system 400, which provides photons 452 in the visible and/or infrared regions to the subject 320, such as via a photon transport system 450, at an illumination zone. After scattering and/or absorbance by the tissue layers 340 of the subject 320, a portion of the photons are detected at a detection zone by a detector system 500. The source system 400 includes one or more light sources, such as any of one or more of a light emitting diode, a laser diode, a black body emitter, and/or a white light source, that emits at any wavelength, range of wavelengths, and/or sets of wavelengths from 400 to 2500 nm. Each source system photon source is optionally controlled in terms of time of illumination, intensity, amplitude, wavelength range, and/or bandwidth. The photon transport system 450 comprises any fiber optic, light pipe, air interface, air transport path, optic, and/or mirror to guide the photons from the light source to one or more illumination zones of the skin surface 330 of the subject 320 and/or to guide the photons from one or more detection zones of the skin surface 330 of the subject 320 to one or more detectors of the detector system 500. Optionally and preferably, the photon transport system 450 includes one or more optical filters and/or substrates to selectively pass one or more wavelength regions for each source element of the source system 400 and/or to selectively pass one or more wavelength ranges to each detector element of the detector system 500. Herein, the reference 310 is optionally an intensity and/or wavelength reference material used in place of the sample and/or is used in a optical path simultaneously measured by the analyzer 110.

Still referring to FIG. 4A and referring now to FIG. 4B and FIG. 4C, the subject 320 optionally and preferably wears the analyzer 110 in the physical form of a watch head, band, and/or physical element attached to the body with a band and/or an adhesive. For example, the analyzer 110, the spectrometer 140, the source system 400, and/or the photon transport system 450 is optionally attached to the subject 320, such as at the wrist or upper arm, using thin affixing layer 460, such as a double sided adhesive 462. Referring now to FIG. 4B, the double sided adhesive 462 optionally contains an aperture 464 therethrough. The photons 452 optionally and preferably pass through the aperture 452 to the skin surface 330 of the subject. The force wave 250 optionally moves the skin surface 330 through the aperture into intermittent contact with the analyzer 110. Optionally, referring now to FIG. 4C, a thin affixing layer 466, such as less than 1, 0.5, or 0.25 mm thick, is continuous in nature in front of the incident surface and/or incident photon coupling zone and/or is continuous in nature in front of the detection zone, where photons exiting the skin surface 330 are detected by the detector system 500. The affixing layer 466 is optionally permeated with a fluid, such as a coupling fluid, an air displacement medium, an optical coupling fluid, a fluorocarbon liquid, a fluorocarbon gel, an index of refraction matching medium, and/or any fluid that increases a percentage of photons from the source system 400 entering the skin surface 330 compared to an absence of the fluid and/or is any fluid that increases a percentage of photons from the tissue layers 340 exiting the detection zone and reaching the detector system 500 as compared to a case where the fluid is not embedded into the affixing layer. Hence, the affixing layer serves several purposes: attaching the analyzer or a portion thereof to the skin surface 330 of the subject 320, coupling forces from the force system 200 to the skin surface 330 of the subject 320, forming a constant sampling interface location on the skin surface 330 of the subject, and/or altering a coupling efficiency, angular direction, and/or reproducibility of coupling of photons enter the skin of the subject 320 and/or exiting the skin surface 330.

Coupled Force System/Spectrometer

Referring now to FIG. 5A and FIG. 5B, the force system 200 is illustrated working in conjunction with the spectrometer 140. Referring now to FIG. 5A, the analyzer 110 is illustrated with the force system 200 being attached to and/or within 1, 2, 3, 5, 10, 20, or 50 mm of the spectrometer 140. Referring now to FIG. 5B, the analyzer 110 is illustrated with the force system 200 being integrated into the spectrometer 140, such as within 20, 10, 5, 2, or 1 mm of the source system 400 of the analyzer 110 and/or in a single housing unit of the analyzer 110.

Several examples are provided that illustrate how the force system 200 alters the tissue layers 340 of the subject 320 and how a selection of detected signals from the spectrometer 140 is performed as a function of time and respective radial separation between the one or more illumination zones and the one or more detection zones, such as using water signal, fat signal, and/or protein signal to determine the correct detection signals to use for noninvasive glucose concentration determination.

EXAMPLE I

Referring now to FIG. 6, a first example of the analyzer 110 using the force system 200 and the source system 400 at the same time and/or within less than 60, 30, 15, 10, 5, or 1 second of each other is provided. In this example, the force system 200 applies a force to the tissue layers 340 at a first time, t₁, when the dermis has a first mean z-axis thickness, th₁. Optionally and preferably, the analyzer 110 acquires signals representative of the tissue layers 340 of the subject 320 using the source system 400 and the detector system 500. Illustrated are three representative photon pathways, p₁₋₃, reaching the detector system 500, such as at a first detector element, a second detector element, and a third detector element, respectively, at the first time, t₁, and/or within less than 60, 30, 15, 10, 5, or 2 seconds from the first time, t₁. Notably, at the first time, the first photon pathway, pi, has an average path that does not penetrate into the dermis 346, while the second and third photon pathways, p₂₋₃, have mean pathways that penetrate through the dermis into the subcutaneous fat 348.

In at least one preferred use of the analyzer, noninvasive glucose concentration determination is performed using a mean photon pathway that penetrates into the dermis 346 and not into the subcutaneous fat 348 and/or uses signal from a detector element at a first/minimal radial distance from the illumination zone, where the first/minimal radial distance is the smallest radial distance observing an increase in a fat signal/dominantly fat related signal, such as from the subcutaneous fat 348, compared to a water signal/dominantly water related signal from skin layers 340 closer to the skin surface 332 than that subcutaneous fat 348. Examples of wavelengths containing dominantly water absorbing signals are wavelengths correlating with the peaks of the water absorbance bands 710, FIG. 7A, and/or peaks of the protein absorbance bands, FIG. 7B, and examples of wavelengths containing an increased fat absorbance to water absorbance ratio when a mean photon path enters the subcutaneous fat 348 are at the fat absorbance bands 720. For instance, a protein band-to-fat band ratio optionally compares the protein absorbance band 730, such as at 1690 nm, with the fat absorbance band 720, such as at 1715 nm, where either range is ±5 or ±10 nm. Still referring to FIG. 6, at a second time, t₂, the force wave 250 from the force system 200 has expanded the dermis layer to a second thickness, th₂, which is at least 0.1, 0.2, 0.3, 0.5, 1, 2, 5, 10, 20, or 50% thicker than the first thickness, th₁, and/or has an increased water absorbance, as measure by the first, second, and/or third detector element of the detector system 500, representative of the first through third photon pathway, p₁₋₃, in the condition of the larger dermis thickness at the second time, t₂, as represented by a fourth, fifth, and sixth photon pathway, p₄₋₆. Notably, the fifth and sixth photon pathways, p_(5,6), with the same illumination zone to detection zone radial distance as the first and second photon pathways, p₁₋₂, have mean photon pathways that penetrate into the dermis 346 and not into the subcutaneous fat 348. Thus, the water-to-fat ratio and/or the protein-to-fat absorbance ratio of the observed signal continues to increase with radial distance for the second and third detectors after the force system 200 increased the thickness of the dermis 346 to the second thickness, th₂.

Again, at least one preferred measurement/metric is a measurement with a higher water-to-fat absorbance ratio and/or a higher protein-to-fat absorbance ratio as the metric indicates that the photons are sampling the dermis 346 without undue sampling of the subcutaneous fat 348, where the metric is used with or without an applied displacement force from the transducer. In this example, at the second time, the water-to-fat absorbance ratio of the fifth optical path, p₅, is greater than observed with the second optical path, p₂, despite have the same source zone-to-detector zone radial distance. Further, in this example a preferred optical signal is from the sixth optical path, th6, at the second time, t₂, with a largest ratio of mean pathlength in the dermis 346 to total mean detected pathlength. For illumination zone-to-detector zone distances established to sample the dermis 346, as discussed infra, determining a current thickness of the protein/water rich dermis 346 yields knowledge of an appropriate glucose illumination zone-to-glucose detection zone, such as for photons in the range of 1500 to 1600 nm, probing the dermis 346 as glucose is soluble in the water rich dermis 346.

Referring now to FIG. 7C, for clarity of presentation and without loss of generality, a particular metrics 760, such as a fat band metric, a protein band metric, and/or a water band metric are illustrated. As illustrated, a first signal 722 related to the fat absorbance band 720 decreases in intensity with radial distance between an illumination zone and a detection zone. The decrease in intensity with radius for a first radial distance, r₁, a second radial distance, r₂, and a third radial distance, r₃, relates dominantly to a decreased photon density as a function of distance from the illumination zone, scattering, and water absorbance. However, a rapid first change in intensity, Δl₁, is observed between the third radial distance, r₃, and the fourth radial distance, r₄, which at wavelengths related to the fat absorbance band 720, such as about 1710 nm, indicates that a larger concentration of fat is observed to begin between the third and fourth radial distances indicating that the mean maximum depth of penetration of the probing photons has crossed from the dermis 346 into the subcutaneous fat 348. Hence, the large first change in intensity, Δl₁, at the fourth radial distance indicates that a radial distance corresponding to a maximum depth of penetration sampling the dermis 346 is the third radial distance, r₃. Similarly, the second signal 732 related to the water absorbance 710 and/or the protein absorbance 720 has a trend breaking second change in intensity, Δl₂, between the third radial distance, r₃, and the fourth radial distance, r₄, which indicates that the second probing photons at a wavelength dominated by a water absorbance, such as at 1450±10, 20, 30, 40, 50, 60, or 70 nm, or a protein absorbance, such as at 1690±5 or 10 nm, are observing a lower concentration of the water and/or protein, such as by crossing the same dermis—subcutaneous fat interface. Hence, any of the metrics related to water, protein, and/or fat are used independently and/or in any mathematical relationship, such as a ratio or derivative, to find a first sample probe geometric distance, between a first illumination zone and a first detection zone, associated with a first maximum mean depth of penetration in the glucose rich dermis layer 346, such as at the first radius, r₃, and/or a second sample probe geometric distance associated with a second maximum mean depth of penetration in the glucose poor subcutaneous fat layer 348, such as at the fourth radius, r₄.

FIG. 7D illustrates increased scattering with decreasing wavelength at a first scattering coefficient, μ_(s1), 740 and a second scattering coefficient, μ_(s2), 750. Optionally and preferably, an expected decrease in observed intensity with increasing radial distance between a given illumination zone and a given detection zone includes use of a scattering coefficient, which is wavelength dependent.

EXAMPLE II

Referring now to FIG. 8, a second example is provided where the analyzer 110 uses the force system 200 to alter the sample 300 to enhance a noninvasive analyte property determination using the spectrometer 140. As above, the force system 200 provides one or more force waves 250 into the subject 320, which alters positions of cells 260 in the dermis 346 relative to the illumination zone of the illumination system 400 and or relative to one or more detection zones associated with a single element detector and/or one or more detectors of an array of detector elements 510. As illustrated, the cells 360 have a first average intercellular distance at a first time, t₁, which is altered by application of the force wave 250 to a second average intercellular distance at a second time, t₂, where the net change in cell position alters detected spectrophotometric absorbance signals at a give detector element of the detector system 500 by greater than 0.01, 0.02, 0.05, 0.1, 0.5, 1, 2, 5, or 10 percent, such as by a change in observed scattering and/or observed absorbance at a fixed radial distance between an illumination zone and a detection zone. Similarly, the average percentage volume of the intercellular fluid 350 in the dermis layer differs by greater than 0.01, 0.02, 0.05, 0.1, 0.5, 1, 2, 5, or 10 percent as a result of the applied force wave(s) 250. All of a change in thickness, change in observed mean pathlength, change in radial distance of detection, change in mean intercellular spacing, change in scattering, and change in water concentration, related to perfusion, are illustrated between the first time, t₁, and the second time, t₂, as a result of the applied force wave 250. Notably, a selected detector signal from the array of detectors 510 changed from a second detector 512/second detector element/second detection system at a first radial distance, r₁, from the illumination zone to a fourth detector 514 at a second radial distance, r₂, from the illumination zone based on the above described larger observed water signal-to-observed fat signal ratio and/or as the second pathlength, b₂, is longer than the first pathlength, b₁, in the dermis layer. Similarly, absorbances of skin constituents, such as protein, albumin, globulin, keratin, and/or elastin increase relative to fat absorbance for the second pathlength, b₂, as the mean pathlength spends more time in the dermis layer compared to the subcutaneous fat layer 348, as described supra.

EXAMPLE III

Referring now to FIG. 9, a third example of using the force system 200 to alter properties of the subject 330 to enhance performance of a noninvasive glucose concentration determination using the spectrometer 140 is provided. In this example, the detector array 510 of the detector system 500 contains n detector elements at differing radial distances from a time correlated illumination zone. For clarity of presentation, the detector array 510 is illustrated with four detector elements: a first detector 511/first detector element/first detector system, a second detector 512/second detector element second detector system, a third detector 513/third detector element/third detector system, and a fourth detector 514/fourth detector element/fourth detector system. At a first time, t₁, the large water absorbance, protein absorbance, and/or protein and water absorbance-to-fat ratio is observed using the second detector 512 having a first illumination zone-to-detection zone radial distance, r₁, and a first mean optical pathway, d₁, penetrating into the dermis 346 with minimal to no mean penetration into the subcutaneous fat 348. However, at a second time, t₂, after the provided force wave 250 has altered the skin of the subject 320, the third detector element is observed, at a selected detection point in time, to have the largest metric for detector selection, such as a smoothly falling observed intensity with radial distance at a fat absorbance wavelength, where a sudden decrease in observed intensity at the fat absorbance wavelength indicates mean penetration of the observed optical pathway into the subcutaneous fat 348, such as at the second radial distance, r₂. Notably, the largest radial distance is selected for a given water, protein, and/or fat based metric as at the larger radial distance a difference between a shortest possible pathlength between the illumination zone and the detection zone, the radial distance, is closest to the largest possible observed pathlength, which is based upon a maximum observable absorbance by a detector type for a fixed number of photons. For example, if the maximum observable absorbance is 3.9 and the absorbance per millimeter is 1.3, then a maximum observable pathlength is 3.0 mm. If the observed radial pathlength is 1.5 mm then a first range of observed pathlengths is 1.5 to 3.0 mm with a difference of 1.5 mm. Hence, a first ratio of observed pathlength difference to radial distance is 1:1 (1.5 mm: 1.5 mm), which is a 100% error. However, if the observed radial pathlength is 2.5 mm, then a second range of observed pathlengths is 2.5 to 3.0 mm with a difference of 0.5 mm. Hence, a second ratio of observed pathlength difference-to-radial distance is 1:5 (0.5 mm: 2.5 mm), which is a second pathlength error of 20% or one-fifth of the pathlength error of the first case. In general, the largest radial distance yielding and intensity-to-noise ratio beyond a threshold, such as 0.5, 1, 1.5 or 2, is preferred as error in a range of observed pathlengths decreases, which reduces the error in b, in Beer's Law: equation 1,

A=molar absorptivity * b * C (eq. 1)

where A is absorbance, b is pathlength, and C is concentration, which is central to visible and near-infrared absorbance and/or scattering models used to determine an analyte property, such as a noninvasive glucose concentration as measured using photons optically probing skin.

Skin State Classification

Skin state is optionally classified using a single force pulse or single impulse function, also referred to herein as a ping. Generally, an applied force, such as the force wave 250 provided by the force system 200, takes time to propagate through the subject 320. The travel time of the force wave varies as a function of state of the body, such as hydration, temperature, glucose concentration, triglyceride concentration, hematocrit and/or any constituent of skin, blood, and/or interstitial fluid. Hence, the amount of time to travel radial distances to force wave detectors is optionally used to classify the state of the subject and/or to map the state of the subject in regions probed by the force wave. For clarity of presentation and without loss of generality, two example of force wave detection are provided here using: (1) a transducer force detector and/or (2) an optical force wave classifier.

EXAMPLE I

Referring now to FIGS. 10(A-C), transducer force detectors are optionally used to detect transit times of the force wave 250 from the force wave input element 210 to one or more detectors of a set of transducer force detectors 260. Generally, a transducer force detector converts mechanical motion, such as passage of the force wave 250 and/or skin movement into a measured electrical signal. Referring now to FIG. 10A, for clarity of presentation and without loss of generality, a first transducer force detector 262, a second transducer force detector 264, and a third transducer force detector 266 are illustrated that represent n transducer based force detectors, where n is a positive integer of greater than 1, 2, 3, 5, 10, or 20. As illustrated in FIGS. 10B and 10C, the n transducer based force detectors are optionally positioned in a linear array, in a two-dimensional array, and/or along arcs, such as at differing radial distances from one or more light sources in the source system 400. Referring still to FIG. 10A, as illustrated, at a first time, the force wave 250 has propagated to the first transducer force detector 262 as a first wave front position 254; at a second time, t₂, the force wave 250 has propagated to the second transducer force detector 264 as a second wave front position 256; and at a third time, t₃, the force wave 250 has propagated to the third transducer force detector 266 as a third wave front position 258. Timing of each wave front to each transducer based force wave detector allows: (1) generation of a sub-surface tissue map of constituents of the skin of the subject 320 using mathematical techniques used for seismic mapping known to those skilled in the art of seismic mapping and/or (2) a classification of state of the subject 320 versus a calibration set of classifying states of force wave propagation radial translation times. For instance, the classification is as simple as slow, medium, or fast translation times to a given transducer detector or a more involved combination of translation times for one or more of: (1) responses at a single detector position and (2) responses at a set of detector positions and/or responses to varying inputs of the force wave, such as time, direction, amplitude, and/or frequency of one or more pings from the force wave input elements and/or time varying induced applied pressure and/or displacement of a portion of the skin of the subject 320 by the force system 200.

EXAMPLE II

Referring now to FIGS. 11(A-C), propagation of the force wave(s) 250, such as force wave fronts 254, 256, 258 is detected using a set of optical detectors and using the results in a manner similar to detecting the force wave 250 using the set of transducer based wave detectors. For instance, as the force wave 250 propagates through the tissue layers 340, the density, absorbance, and/or scattering of voxels of the skin of the subject 320 change, which alters an observed mean optical path between a given source of photons and a photon/photonic detector. One or more sources of the source system 400 coupled to the array of optical detector elements 510 via the subject 320 is optionally used to detect propagation times of the force wave(s) 250. For clarity of presentation and without loss of generality, a first optical detector 521, a second optical detector 522, and a third optical detector 523 are illustrated that represent n optical detectors, where n is a positive integer greater than 0, 1, 2, 3, 5, 10, 15, 16, 20, 25, 100, 500, 1000, and 5000. As illustrated in FIGS. 11B and 11C, the n optical detectors are optionally positioned in a linear array, in a two-dimensional array, and/or along arcs, such as differing radial distances from one or more light sources in the source system 400 and/or from one or more force wave sources. Notably, one or more detectors of the array of optical detector elements 510 are optionally and preferably used to detect photons from the source system 400 during a measurement phase of an analyte and/or tissue property with or without a tissue classification step. As illustrated, the first optical detector 521 detects a first optical signal, modified by the force wave 250, with a first pathlength, pi, at a given point in time; the second optical detector 522 detects a second optical signal, modified by the force wave 250, with a second pathlength, p₂, at the given point in time; and the third optical detector 523 detects a third optical signal, modified by the force wave 250, with a third pathlength, p₃, at the given point in time. Each detected optical signal contains absorbances due to any sample constituent, such as water, protein, fat, and/or glucose and/or is representative of state of the tissue, such as a measure of scattering and/or temperature. As the force wave(s) propagate through the tissue, the first, second, and third pathlengths, p₁, p₂, p₃, vary. Hence, the state of the subject 320 is optionally characterized and/or mapped in a manner similar to the transducer wave detection classification and/or mapping; however, optical signals with chemical meaning are used in the process, such as detected intensity, absorbance, and/or scattering related to temperature, one or more tissue layer properties, collagen, elastin, water, albumin, globulin, protein, fat, hematocrit, and/or glucose, such as a concentration, change in tissue state, or a physical structure.

Referring again to FIG. 11A and FIG. 12A, the applied pressure/force wave/displacement optionally generates a gap and/or varies an applied pressure at a first interface 305 of the source system 400 and the skin surface 330 and/or at a second interface 390 of the detector system 500 and/or any element thereof and the skin surface 330. A resulting air gap between the analyzer 110 and the subject 320 and/or a time varying change between an air gap and contact between the analyzer 110 and the subject 320 is used to determine times of contact/relative contact, which is in turn optionally and preferably used in a selection of detected signals step, described infra. For example, loss of optical contact yields a sudden increase in observed intensity in a wavelength region of high absorbance, such at as region dominated by water absorbance in the range of 1350 to 1550 nm, 1400 to 1500 nm, and/or within 5, 10, 15, 25, and/or 50 nm of 1450 nm. Removal of non-contacting signals aids in the development of an outlier analysis algorithm and/or in determining state of the tissue and/or in determination of a degree of applied force from the source system 400, detector system 500, and/or analyzer 110 to the skin surface 330 of the subject 320 as a function of time and/or position.

Force Wave/Optical Probe Analyte State Determination

Referring now to FIG. 12, a process of determining an analyte property, such as a glucose concentration, using one or more optical signals optionally and preferably modified by an applied force, force wave, and/or displacement is provided.

Referring still to FIG. 12, in a process, such as a first process or a second process, a force is applied 1210, such as in the form of a force wave and/or displacement induced force wave. For example, the force wave/displacement is generated with a transducer to generate application of a transducer force 1212, which is a single ping 1214/displacement and/or a series of pings and/or is a force/displacement varied in frequency 1216 and/or varied in amplitude 1218, such as via a controller, such as a main controller of the analyzer 110. Subsequently, the force wave 250/tissue displacement induced pressure propagates in the sample 1220.

Referring still to FIG. 12, in another process, such as a first or second process, a result of the tissue displacement induced force wave is measured and/or detected 1230, such as through a transducer force detection 1232 and/or an optical force detection 1234.

Referring still to FIG. 12, in still another process, such as a second and/or third process, selection of a sub-set of detected signals 1240 is performed, such as a function of position 1241, time 1242, detector 1243, contact 1244, pressure 1245, and/or spectroscopic response 1246 and an analyte state is determined 1250, such as via generation of a calibration 1252 and/or use of a generated calibration in a prediction step 1254.

Multiple-Sensor System

Referring again to FIG. 4A and referring now to FIG. 13, the analyzer 110 optionally comprises multiple sub-sensor systems that operate independently to collect data but operate in concert for determination of state of the subject 320. For instance the spectrometer 140 optionally comprises a first spectrometer version/system 142 connected/affixed to a first part of the subject 320, such as on the arm of the subject 320, and a second spectrometer system/version 144 connected/affixed to a second part of the subject 320, such as on the leg of the subject 320. Optionally, the spectrometer 140 is affixed to any part of the body, such as an ear lobe, webbing of the hand, forehead, torso, limb, arm, or leg.

Still referring to FIG. 13, generally, the spectrometer 140 refers to n spectrometers/analyzers, where each of the n spectrometers optionally and preferably collects data independently, where n is a positive integer, such as 1, 2, 3, 4, 5, or more. Optionally, each of the n spectrometers collect and analyze data independently. However, preferably, each of the n spectrometers collect data and after little or no pre-processing, collected data is sent to the analyzer 110, a central processor, a personal communication device, such as a cell phone 122, and/or to the web for further processing, which allows a central system to process data from the multiple sub-spectrometer systems.

Still referring to FIG. 13, optionally, each of the n spectrometers are of the same type and design. However, preferably, each of the n spectrometers are distinct in type and/or design. For instance, the first spectrometer version 142 comprises first sources, optics, and detectors that are directed to measurement of a first constituent/property of the subject 320 and the second spectrometer version 144 comprises second sources, optics, and detectors that are directed to measurement of a second constituent/property of the subject 320.

Still referring to FIG. 13, for example, the n spectrometer systems are optionally and preferably configured to interface to separate portions of the body and/or to measure separate and/or overlapping properties/constituents of the subject 320, such as percent oxygen saturation, heart rate, heart rate variability, glucose concentration, protein concentration, fat, muscle, protein concentration, albumin concentration, globulin concentration, respiration rate, an electrocardiogram, blood pressure, and/or body temperature and/or environmental temperature and/or acceleration of the subject 320, such as to indicate a fall of the subject 320 and/or an interfering movement of the subject 320 that affects the measurements of the one or more spectrometers 140.

Still referring to FIG. 13, herein, for clarity of presentation and without loss of generality, the spectrometer 140 is illustrated as a noninvasive glucose concentration analyzer. However, the spectrometer 140 optionally measures any constituent of the body noninvasively, in a minimally invasive manner, and/or operates in conjunction with a noninvasive, minimally invasive, and/or invasive reference system, such as for calibration and quality control procedures. Examples of a first spectrometer version 142 and a second spectrometer version 144 determining an analyte property is provided, infra.

EXAMPLE I

Referring still to FIG. 13, an example of interfacing 1300 the analyzer 110 to an arm 370 of the subject 320 is illustrated. As illustrated, a first analyzer/spectrometer version 371 of the analyzer 110 is coupled to a section of an upper arm 372 of the subject's arm and a second analyzer/spectrometer version 373 of the analyzer 110 is coupled to a forearm/wrist 374 of the patient's arm 320. Notably, the first analyzer version 371 interfaces to the subject 320 at a first interface zone along a first z-axis perpendicular to a first x/y-axis plane that is tangential to the subject 320 and that is independent and different from a second interface of the second analyzer version 373, which interfaces to the subject 320 along a second z-axis perpendicular to a second x/y-axis system that is tangential to a second interface zone of the subject. Generally, n analyzers 110, optionally linked to a single main controller 112, interface to n interface zones of the subject 320, where the main controller 112 is optionally and preferably electrically, mechanically, and/or communicatively linked with any and preferably all subsystems of the analyzer 110 and is used to control the analyzer 110, such as via computer hardware and associated software.

EXAMPLE II

Still referring to FIG. 13, each of the analyzers interfacing to the subject 320 optionally comprise any system of the analyzer 110. As illustrated, the first analyzer version 371, which is an example of the analyzer 110 comprises three analyzer versions, illustrated as the first spectrometer version 142, the second spectrometer version 144, and the third spectrometer version 146. As illustrated, the first spectrometer version 142, optionally in the form of a watch head, interfaces to the subject 320 along a first z-axis perpendicular to a first x/y-plane, which tangentially touches the upper arm 372 at a first interface point; the second spectrometer version 144 has the form of a watch band link and interfaces to the subject 320 along a second z-axis perpendicular to a second x/y-plane, which tangentially touches the upper arm 372 at a second interface point; and the third spectrometer version 146, optionally in the form of a watch band attachment, interfaces to the subject 320 along a third z-axis perpendicular to a third x/y-plane, which tangentially touches the upper arm 372 at a third interface point. Each of the three spectrometer versions 142, 144, 146 are optionally attached to the upper arm 146 via double-sided adhesives and are thus attached in the manner of a sticker. As illustrated, the three spectrometer versions 142, 144, 146 are attached to the upper arm 372 with a flexible band 148, such as a watch band or an elastic band. The individual spectrometer versions 142, 144, 146 are optionally connected using one or more hinge components and or rotating connectors. The individual spectrometer versions 142, 144, 146 are optionally replaceably connected to the subject along separate planes forming angles therebetween of greater than 1, 2, 5, 10, 15, 25, or 25 degrees. The hinge allows tangential interfacing of illumination zones of the respective spectrometer version along a curved surface of the subject 320. Optionally, the hinge allows for rotation of a first spectrometer unit relative to a second spectrometer unit to maintain tangential contact of the illumination zones with the subject 320 as the skin of the subject moves, such as by allowing a rotation of greater than 0.1, 0.5, 1, 2, or 5 degrees. The multiple planes of attachment of the analyzer 110 to the subject 320 allow attachment of multiple sources and/or detectors to the subject 320 along a curved skin surface of the subject 320, such as around the upper arm 372 and/or the lower arm 374, as illustrated with the second analyzer/spectrometer version 373 attached to the wrist of the subject 320, with minimal applied tissue deformation forces at each of the analyzer/subject interface zones. Reduced forces, such as an applied mass, stress, and/or strain aids precision and/or accuracy of the analyzer 110 by reducing movement of fluids within the tissue layers 340 of the subject 320, reducing changes in pathlength, and/or reducing changes in pressure induced scattering of light.

EXAMPLE III

Still referring to FIG. 13, in a first case, each of the first spectrometer version 142, second spectrometer version 144, and third spectrometer version 146 optionally contain all of the functionality of the analyzer 110. However, optionally, one or more optical sources are in one interfacing aspect of the first analyzer version 371, such as in the second spectrometer version 144, without any functional optical detectors in the second spectrometer version 144. In this case, the optical detectors are in a second interfacing aspect of the first analyzer version 371, such as in the first spectrometer version 142. For clarity of presentation and without loss of generality, a particular example is provided. In this example, the detector system 500 is positioned in the analyzer 110 in the first spectrometer version 142 along with optional illuminators of the source system 400. However, the source system also includes photon sources in the second spectrometer version 144, such as in a watch band link position. In this manner, photonic illuminators with short optical distances to the detector system 500 are positioned in the first spectrometer version 142, such as in close proximity to the detector system 500. For instance, photonic sources emitting in wavelength ranges: (1) with an optical absorbance of greater than one unit per millimeter of pathlength and/or (2) in the 1350 to 1560 nm range, such as within 25 mm of 1510, 1520, 1530, or 1540 nm are positioned near the detector system 500, such as in the same housing as the detector system 500, in the first spectrometer version 142, and/or with a radial distance between an illumination zone and a detection zone of less than 10, 8, 6, 5, 4, 3, 2, 1.5, or 1 millimeters. However, photonic sources emitting in lower absorbance regions, such as from 400 to 1350 nm and/or 1565 to 1800 and/or in regions of absorbance by skin at a level of less than one absorbance unit per millimeter of pathlength are positioned in the second spectrometer version 144, thus giving the photons a longer pathlength to the detector system 500 in the first spectrometer version 142. The longer selected pathlength, as selected by a detector element of the detector system 500, from a given source reduces a range of observed pathlengths by photons from the given source, as described supra. Further, each spectrometer version 142, 144, 146 allows an independent mean photon path entering the skin of the subject 320 to be perpendicular to the subject 320 despite the radius of curvature of the skin of the subject 320 as the differing spectrometer versions 142, 144, 146 are each positioned with an x/y-plane interface tangential to the local curvature of the skin of the subject 320, such as at different positions on a watch band equivalent. Optionally and preferably, the x/y-planes tangential to the subject 320 at local sample interface sites for the n interface points of the analyzer 110, such as the first interface location of the first spectrometer version 142, the second interface location of the second spectrometer version 144, and the third interface location of the third spectrometer version 146 are separated by greater than 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 millimeters as measured along the skin surface. Hence, second photon sources for providing second wavelengths for measuring oxygen and/or scattering of light, such as from 400 to 1300 nm, are optionally placed in a second housing along a second position of the watch band while first photon sources for providing first wavelengths, such as at glucose absorbing wavelengths from 1500 to 2400 nm, are optionally placed in a first housing proximate detector elements, where the detector elements in the first housing detect photons from second, third, . . . , n^(th) housings, such as along a circumferential band around a curved body part, where n is a positive integer greater than 1, 2, or 3.

EXAMPLE IV

In the first spectrometer version 371 of the analyzer 110, three sample interface zones are used, a first sample interface zone, such as the back of a watch zone where the source system 400, force system 200, and/or a first set of optics, such as in the first spectrometer version 142, interface to the subject 320; a second interface zone, such as where a second set of optics, such as in the second spectrometer version 144, interface to the subject 320; and a third interface zone, such as where a third set of optics, such as in a third spectrometer version 146, interface to the subject 320. Generally, any number n of sets of optics interface to the subject 320 to yield n sets of data on a state of the subject 320 where n is a positive integer, such as 1, 2, 3, 4, 5 or more. Optionally, the n sets of optics generate simultaneous data on a single state of the subject 320. However, each sub-set of optics in the n sets of optics are optionally configured to measure the same analyte and/or different analytes, such as one of more of percent oxygen saturation, heart rate, heart rate variability, glucose concentration, protein concentration, fat, muscle, protein concentration, albumin concentration, globulin concentration, respiration rate, an electrocardiogram, blood pressure, body temperature, environmental temperature, and acceleration of the subject 320.

Depth Resolution

Photons scatter in tissue. However, a mean photon path between an illumination zone and a detection zone has a mean/medium/average depth of penetration into the skin layers 340 and glucose is present at differing concentrations as a function of depth into the skin layers 340. A target zone of probing photons is the epidermis 344 and/or dermis 346 between the stratum corneum 342 and the subcutaneous fat 348. Targeting these well perfused tissue layers is described herein by way of non-limiting examples.

EXAMPLE I

Referring now to FIG. 14A, an example of a probe tip 1400 of the source system 400 of the analyzer 110 is presented. The probe tip 1400 has a tissue contacting surface 1410 and at least one illumination zone of a set of illumination zones 1420. For clarity of presentation and without loss of generality, a single illumination zone is illustrated which is optionally and preferably one illumination zone of a plurality of illumination zones, such as where a given illumination zone is a surface area of the skin/probe tip interface illuminated by a given source, such as a given light emitting diode. More particularly, 2, 3, 4, or 5, or more, light emitting diodes/laser diodes couple to the skin, optionally via intervening optics of the photon transport system 450, to illuminate a corresponding second, third, fourth, and fifth, or more, skin/probe tip interface areas, referred to herein as illumination zones. Similarly, a given detector element optically couples, such as by the photon transport system 450 to a given surface area of the skin/probe tip interface, which is referred to as a detection zone. More particularly, 2, 3, 4, or 5, or more, detector elements, of the detector system 500, optically interface, such as through optics of the photon transport system 450 with the skin, to detect photons emitting from a corresponding second, third, fourth, and fifth, or more, skin/probe tip interface area, referred to herein as detection zones. A mean optical path for a set of photons is a mean pathway through the tissue layers 340 of the subject 320 between a given illumination zone and a given detection zone. Optionally, the probe tip 1400 is of any geometry. Optionally, illumination zones are of any pattern on the probe tip 1400. Optionally, detection zones are of any layout on the probe tip 1400.

EXAMPLE II

Referring still to FIG. 14A and referring now to FIG. 14B, resolution of a mean depth of penetration of probing photons between an illumination zone and rings of detectors 1430 is provided. As illustrated, a first ring of detectors 1432, coupled to a first set of detection zones, is at a first radius, r₁, from the illumination zone and a second ring of detectors 1434, coupled to a second set of detection zones, is at a second radius, r₂, from the illumination zone. For clarity of presentation and without loss of generality, the detectors and detector zones are illustrated with the same circular graphical representation herein. Further, the circular graphical representations are optionally illustrative of the ends of fiber optics coupled to corresponding detectors or sources. At close distances having an observed absorbance of less than one, the mean depth of penetration of probing photons increases with radial distance. The first and second ring of detectors 1432, 1434 are separated by a radial distance difference, Δr₁. Referring now to FIG. 14B, the first ring of detectors 1432 corresponds to a first mean optical path 1472 having a first depth of penetration into the tissue layers 340 and the second ring of detectors 1434 corresponds to a second mean optical path 1474 having a second depth of penetration into the tissue layers 340. As illustrated, for a first radial detector 1482 at the first radial distance, r₁, the maximum depth of the first mean optical path 1472 and the second mean optical path, for a second radial detector 1484 at a second radial distance, r₂, have a depth of penetration difference, Ad/. Notably, the second ring of detectors 1434 is spatially positioned at a closest linear distance, the line passing through an illumination zone of the set of illumination zones 1420, to the first ring of detectors 1432. Thus, the best resolution of depth is the depth of penetration difference, Δd₁, corresponding to a first range of tissue thicknesses 1482. However, in many cases, as the thicknesses of the epidermis 344 and dermis 346 changes with applied pressure, force, hydration, spatial orientation, movement, and/or changes in blood constituent concentration, the targeted dermal layers are not resolved using the best resolution of concentric detector rings with a difference in radial distance, Δr₁, to the illumination zone corresponding to the resolved depth, Δd₁.

EXAMPLE III

Referring still to FIG. 14A and FIG. 14B and referring now to FIG. 14C, a comparison of resolution of a mean depth of penetration of probing photons between an illumination zone and rings of detectors 1430 and arcs of detectors 1450 is provided. Herein, an arc of detectors is a set of detectors along a curved path of multiple radial distances from an illumination zone. The arced path is not an arc of a circle. Rather, the arced path is along a spiral and/or curve covering a range of radial distances from an illumination zone. As illustrated an arc of detectors 1450, along an optional arc layout 1462, starts at the first radial distance, r₁, of the first ring of detectors 1432 and ends at the second radial distance, r₂, of the second ring of detectors. While the first and second ring of detectors have a first linear radial distance difference, r₁, that is based on the size of the detector element housing, fiber optic, and/or detection zone, the illustrated arc of detectors 1450 has a second linear radial distance difference, r₂, that is smaller than, Particularly, with the seven illustrated detectors in the arc of detectors, the second linear radial distance, r₂, is one-seventh that of the first radial distance, Generally, the difference in radial distance is better than ½, ⅓, ¼, ⅕, . . . , 1/n that of the spatially constrained concentric rings of detectors for n detector elements in an arc bounded by the first and second radial distances, r₁ and r₂, of the concentric rings of detectors, where n is a positive integer of greater than 2, 3, 4, 5, 10, or 20. Comparing now the first and second mean depths of penetrations 1472, 1474 for the first and second ring of detectors 1432, 1434 and the first and second detector 1482, 1484, with the range of mean depths of penetrations in FIG. 14C corresponding to the individual illumination zones, of the set of illumination zones 1420, to detection zones of detector elements in the ring of detector elements 1450, the enhanced resolution is illustratively obvious. Particularly, the above described first resolved depth, Δd₁, corresponding to the first and second ring of detectors 1432, 1434 is seven times larger than a second resolved depth, 66 d₂, between a third mean path 1437 and a fourth mean path 1474 corresponding to the second radial detector 1484 and a closest intermediate radial detector 1486, two detector elements in the arc of detectors 1450. Particularly, a second range of tissue thicknesses 1484 is thinner than the first range of tissue thicknesses 1482, described supra. Generally, the difference in resolved tissue depth is better than ½, ⅓, ¼, ⅕, . . . , 1/n that of the spatially constrained concentric rings of detectors for n detector elements in an arc bounded by the first and second radial distances, r₁ and r₂, of the concentric rings of detectors, where n is a positive integer of greater than 2, 3, 4, 5, 10, or 20. Thus, arcs of detection zones corresponding to arcs of detectors and/or coupling optics, such as fiber optics, spanning a range of radial distances from an illumination zone yield an enhanced resolution of tissue depth. Further, as described supra, dynamic selection of signals from detector elements radially inward from an outwardly positioned detector element observing a disproportionate increase in a fat band absorbance, which is an example of a spectroscopic marker, from the subcutaneous fat 348, at a greater depth than the targeted dermis 346, yields the largest radial distance observing the desired/targeted dermal layers. Further, as the epidermis 344 and dermis 346 change in thickness, such as due to subject movement, orientation, and/or hydration, and/or changes in body chemistry, the range of resolved depths of penetration corresponding to the range of radial distances between the illumination zone and individual detection zones allows dynamic selection of source-to-detector distances currently probing the desired dermal layers, such as the epidermis 344 and the dermis 346.

Depth/Location Selection

Referring now to FIGS. 15A, 15B, 15C, 15D, 16A, 16B, 16C, 16D, and 17, a method and apparatus are described for selecting, as a function of wavelength, illumination zone-to-detection zone distances yielding a common and/or overlapping depth of sampling and/or position of sampling. In the examples provided, for clarity of presentation and without loss of generality, notation of a first, second, third, . . . , n^(th) source and/or detector is used where the n^(th) source/detector in one example is optionally distinct from the n^(th) source/detector in another example. Further, it is understood that skin layers are not homogenous and that variations occur from tissue voxel to tissue voxel. However, sampling a common depth and location aids in measuring a common sample state within the non-homogenous tissue layers, especially when used in conjunction with one or more of: a larger illumination zone, a larger detection zone, sample movement relative to the analyzer, and/or analyzer movement relative to the sample.

EXAMPLE I

Referring now to FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D in this first example, a common depth selection system 1500 and method of use thereof is described.

Referring now to FIG. 15A. The spectrometer includes a first source 401/source element, illuminating a first illumination zone of the set of illumination zones 1420. Light from the first illumination zone is detected by a first set of detectors 1510, such as a first detector 511 detecting photons at a first detection zone, a second detector 512 detecting photons at a second detection zone, a third detector 513 detecting photons at a third detection zone, and/or a fourth detector 514 detecting photons at a fourth detection zone. Herein, the sources and detectors are illustrated at the skin surface for clarity of presentation and without loss of generality. However, it should be understood that the actual source and/or detector elements, are optionally positioned anywhere, and are optionally and preferably optically coupled to their respective source zone/detection zone via air and/or one or more optics. For instance, a source optionally uses a fiber optic, or any optic, to deliver light from the source to the outer skin surface 330. Similarly, a detector optionally uses any optic to deliver a portion of the photons emitting from a detection zone, optically visible to the detector, to the detector element.

Referring still to FIG. 15A and referring now to FIG. 15B, depths of penetration of photons passing from the set of illumination zones 1420 to the second set of detectors 1520 is illustrated. As illustrated, photons have a first mean path, pi, from the first illumination zone associated with and/or optically linked to the first source 401 and to a first detection zone associated with and/or optically linked to the first detector 511. Similarly, as illustrated, photons have a second mean path, p₂, from the first illumination zone associated with and/or optically linked to the second source 402 and to a second detection zone associated with and/or optically linked to the second detector 512. Similarly, a third mean path, p₃, and fourth mean path, p4, link the third detector 513 and fourth detector 514 to the first source 401. It should be understood that the actual mean optical paths are not clear arcs as illustrated and the mean paths rather illustrate the point that differing illumination zone-to-detector zone distances have differing coupling mean pathways and/or the pathways probed differing sample layers at different weights. As illustrated, the second mean path, p₂, is the longest path in the dermis layer 346 that does not substantially pass through the subcutaneous fat layer 348, which is a first selection metric, which is an example of a selection metric. In this example, the second mean path, p₂, is a first selected path based upon the selection metric. Selection metrics are optionally generated using one or more readings related to absorbance of fat, water, and/or protein. It should be understood that the first source 401 is illustrated at a first illumination zone only for clarity of presentation and the first source is optionally and preferably embedded into the analyzer 110 and coupled to the illustrated illumination zone with or without a coupling optic and that this general presentation approach holds for each source and similarly holds for each detector where a given detector is illustrated at a detection zone where optionally and preferably the given detector is configured to view the detection zone with or without an intervening optic.

Referring still to FIG. 15A and FIG. 15B, depths of penetration of photons passing from the set of illumination zones 1420 to the second set of detectors 1520 is further described for a second wavelength range, where photons from the first source 401 have a first distribution of intensity as a function of wavelength and a first mean wavelength and photons from a second source 402 have a second distribution of intensity as a function of wavelength and a second mean wavelength differing from the first mean wavelength by greater than 1, 2, 5, 10, 20, 50, or 100 nm. Photons from the second source 402 interact with tissue differently from the photons from the first source 401, in terms of absorbance and scattering, which results in differing total pathlengths and sample pathlength in tissue layers, such as the epidermis 344, dermis 346, and/or subcutaneous fat 348. As illustrated, a second set of wavelengths, from the second source 402, reaching the surface of the skin 330 have longer observed mean pathlengths than a first set of wavelengths, from the first source 401, reaching the outer skin surface 330 or surface of the skin. For instance, the second set of wavelengths cover a wavelength range with lower overall absorbance of the sample constituents, such as a lower water absorbance, than the first set of wavelengths. As above, photons from the second source 402 have a fifth mean optical path, p5,/fifth path/fifth mean path; a sixth mean path, p₆; a seventh mean path, p₇; and an eighth mean path, p₈, to a fifth, sixth, seventh, and eighth detection zone observed by a fifth detector 515, a sixth detector 516, a seventh detector 517, and an eighth detector 518, respectively. Generally, any number of sources, m; any number of detectors, n; and/or any number of radial distances, r, are optionally used, where m and n are positive integers and r is a distance of greater than 0.01, 0.1, 0.5, 1, 1.5, 2, 3, 4, 5, or 10 millimeters.

Still referring to FIG. 15A and FIG. 15B, using the same criteria of the longest observed path in the dermis layer 346 that does not substantially pass through the subcutaneous fat layer 348, the seventh path, p₇, is a second selected path based upon the first selection metric. The first selected path, p₂, and the second selected path, p₇, are both weighted to a common sample depth, the dermis 346. Hence, (1) the first source 401 coupled to the second detector 512 and (2) the second source 402 coupled to the seventh detector 517 each have weighted sampling to a common sample, the dermis 346. In stark contrast, at a common radial distance, such as observed at the first detector 511 and fifth detector 515, the mean photons sample differing samples; the first source 401 dominantly sampling both the epidermis 344 and dermis 348, as illustrated by the first path, p₁, and the second source 402 dominantly sampling the epidermis 344, as illustrated by the fifth path, p₅.

Referring now to FIG. 15C, the chosen radial separations of the sources and detectors, such as chosen in the preceding paragraph of this first example, are illustrated in an optional second probe configuration 1502. Particularly, (1) a first selected radial distance, r₁, between the first source 401 and the selected second detector 512 is maintained and (2) a second radial distance, r₂, between the second source 402 and the selected seventh detector 517 is maintained without the need of the additional detector elements. Thus, for a static sample, the benefits of the common depth selection system 1500 are maintained in the second probe configuration 1502.

EXAMPLE II

Referring now to FIG. 16A, FIG. 16B, FIG. 16C, and FIG. 16D in this second example, a common sample position selection system 1600 and method of use thereof is described, where the common sample position is optionally and preferably at the common depth, such as the dermis, described supra.

Referring still to FIG. 16A and FIG. 16B, the common sample position system 1600 is first described through an illustrated addition of two additional wavelength ranges to the common depth selection system 1500, described supra, where the resulting four wavelength ranges have four distinct mean wavelengths reaching the detector and where each of the four distinct mean wavelengths are separated from each other by at least 10 nm. Particularly, the separation of the first source 401 from the second detector 512 by the first radial distance, r₁, is maintained from the prior example as is the separation of the second source 402 from the seventh detector 517 by the second radial distance, r2. Added to the illustration is a separation of the third source 403 from the sixth detector 516 by a third radial distance, r₃, and a separation of a fourth source 404 from a ninth detector 519 by a fourth radial distance, r₄. Notably, all of the illustrated source-to-detector distances are selected, such as by the method of the first example and/or through use of a metric, such as a measure of water, protein, and/or fat absorbance, to sample a common depth, which as illustrated is the dermis 346. An apparatus setting each of the four wavelength ranges to a same mean lateral x-position and/or y-position is described, infra.

Referring now to FIG. 16C and FIG. 16D, the four source-to-detector distances, described supra, selected to sample a common depth, such as the dermis, are positioned in a probe face to yield a common lateral position at depth within the tissue or a common central zone 1610 at the surface. Particularly, a mean position between each of the source-to-detector positions is overlaid on at a common x-axis, as illustrated, and/or a common y-axis position to within less than 2, 1, 0.5, 0.4, 0.3, 0.2, or 0.1 mm.

Referring now to FIGS. 15(A-D) and FIGS. 16(A-D), while skin is not homogeneous, overlapping the photonic pathways of a set of differing wavelengths detected by a set of detectors, in terms of a common depth and/or a common position, yields a higher probability of sampling a common tissue state.

EXAMPLE III

Referring now to FIG. 17, in this third example, a common depth selection and common detector system 1700 and method of use thereof is described.

Still referring to FIG. 17, generally, different wavelengths of light, in the range of 1100 to 2500 nm, have different mean depths of penetration into skin due to skin having a large range of absorbance and/or a large range of scattering as a function of wavelength. For instance, first photons at a first wavelength where the skin absorbs heavily, such as at and/or near a peak of the water absorbance bands 710, at 1450 nm, and/or at 1900 nm, have a shallow maximum mean depth of penetration into the skin layers, such as only penetrating into the epidermis 344. Similarly, second photons at wavelengths having a lower absorbance, such as on a shoulder of the water absorbance bands 710, have a mean detected photonic path that penetrates deeper into the skin, such as into the dermis 346. Again similarly, third photons having wavelengths at a still lower absorbance, such as at and/or near a valley of the water absorbance bands 710, have a mean detected photonic path that penetrates still deeper into the skin, such as into the subcutaneous fat 348. Hence, traditional systems sampling different wavelength ranges sample different mean sample depths.

Generally, a magnitude of absorbance of the skin is inversely related to a maximum mean depth of penetration of detected photons into the skin and water absorbance, optionally modified by scattering, dominates an overall magnitude of absorbance of the skin due to waters high absorbance in the range of 1100 to 2500 nm relative to other skin constituents.

As a result of sampling differing sample depths, errors are introduced into traditional analyzers, such as a noninvasive glucose concentration analyzer, as the skin layers 340 differ in both chemical and physical makeup and hence the wavelengths actually probe different samples. Here, a system of sampling a common skin layer is described, where optionally and preferably signals with differing illumination zone-to-detector zone distances are measured with a common detection zone optically linked to a detection system, such as a detector and/or a detector optically coupled to the common detection zone with one or more optics.

Referring again to FIG. 17, for clarity of presentation and without loss of generality, a specific case of a range of wavelengths sampling a common skin layer is described. Particularly, in this case the first source 401 comprises a higher relative sample absorbance, such as within 10, 20, 30, 40, 50, 75, or 100 nm of a peak water absorbance at 1450 or 1900 nm and a first detected signal of photons from the first source 401 is dominated by a water signal at a first radial distance, r₁, to the first detector 511, where the first radial distance is set at a distance yielding a maximum mean photonic path in the dermis 346. Further, in this case the second source 402 comprises a mid-range sample absorbance, such as within 10, 20, 30, 40, or 50 nm of a mid-point absorbance of the peak water absorbance bands, such as at 1410, 1520, 1870, 2020, or 2380 nm, where the second detected signal of photons from the second source 402 is still dominated by a water signal at a second radial distance, r₂, but, the second wavelength range also samples another sample constituent, such as glucose, while still yielding a maximum mean photonic path in the dermis 346. Notably, to sample the same depth as the first illumination zone-to-detection distance, while being as a second wavelength of lower overall absorbance, the second radial distance is larger than the first radial distance. Still further, in this case the third source 403 comprises a still lower sample absorbance, such as within 10, 20, 30, or 40 nm of a first quartile point of the peak water absorbance bands, such as at 1380, 1550, 1850, 2090, or 2350 nm, where the third detected signal of photons from the third source 403 is still dominated by a water signal at a third radial distance, r₃, but, the third wavelength range also samples another sample constituent, such as protein, while still yielding a maximum mean photonic path in the dermis 346 by having the third radial distance be longer than the second radial distance, which is in turn larger than the first radial distance. Yet still further, in this case the fourth source 404 comprises the still lower sample absorbance, such as within 10, 20, 30, or 40 nm of the first quartile point of the peak water absorbance bands, such as at 1380, 1550, 1850, 2090, or 2350 nm, where the fourth detected signal of photons from the fourth source 404 is still dominated by a water signal at a fourth radial distance, r₄, but, the fourth wavelength range also samples another sample constituent, such as the subcutaneous fat 348, by having the fourth radial distance be further from detection zone relative to the third radial distance. Stated again, although the third source 413 emits third detected photons at a higher water absorbance wavelength/value relative to a lower water absorbance/value in a range of fourth detected photons, the maximum mean depth of the fourth photons penetrates further into the sample, such as the subcutaneous fat 348 relative to the dermis 346 probed by the third photons, due to the larger radial distance of the fourth radial distance relative to the third radial distance. Optionally, the third radial distance is configured to measure protein, such as at a wavelength with 5, or 10 nanometers of 1690 nm. Optionally, the fourth radial distance is configured to measure subcutaneous fat, such as at a wavelength with 5 or 10 nanometers of 1710 nm.

Still referring to FIG. 7A, optionally, a common detection zone linked to a common detector system is used to sample light from the first, second, third, and fourth radial distances from the first source 401, the second source 402, the third source 403, and the fourth source 404, respectively. Generally, targeting skin layers 340 is demonstrated for each of a set of range of wavelength ranges, where each member of the set of wavelength ranges comprising a source-to-detector distance set by prior analysis, skin absorbance, water absorbance, and/or scattering. Notably, enhanced precision of depth targeting is achieved by measuring a range of illumination zone-to-detection zone distances. In this example, the higher relative absorbance is at least 20, 30, 40, 50, 75, or 100 percent higher than the mid-range absorbance. In this example mid-range absorbance is at least 20, 30, 40, 50, 75, or 100 percent higher than the lower quartile absorbance. In this example, the second radial distance is at least 0.2, 0.3, 0.4, 0.5, 0.75, or 1 mm larger than the first radial distance; the third radial distance is at least 0.2, 0.3, 0.4, 0.5, 0.75, or 1 mm larger than the second radial distance; and/or the third radial distance is at least 0.2, 0.3, 0.4, 0.5, 0.75, or 1 mm larger than the fourth radial distance.

Optionally and preferably, the sources are light emitting diodes, laser diodes, and/or provide a narrow band of light through use of a long pass filter, a short pass filter, a bandpass filter, and/or an optical filter. Generally, a given optional source system intended to illuminate a given wavelength region may provide additional photons at other regions of higher water absorbance, where the water absorbance blocks the additional photons. Generally, a given source intended to illuminate a given wavelength range, in the 1100 to 2500 nm wavelength region, does not provide more than 20, 10, 5, or 0 percent of the light in a lower absorbing region. For instance, a source intended to provide photons for analysis of fat at 1710 nm may provide photons from 1700 to 1720 nm, where photons at 1900 to 2000 nm are optionally provided as they are absorbed by water in the skin, and where photons at 1500 to 1650 nm are provided only at low intensity or are optically blocked as the water of the skin allows more of the photons in the 1500 to 1650 nm region to reach the detector and are thus avoided for analysis of the fat. Similarly, each intend wavelength, for analytes such as water, protein, and glucose, have similar source requirements for a common detector system. In an optional case where one or more detector systems has blocking optics for different wavelengths, the limitations on the source systems described herein is removed.

EXAMPLE IV

Referring now to FIG. 18, in this third example, a common depth selection and common sample position analyzer 1800 and method of use thereof is described. Generally, for each member of a set of sources a common mid-zone 999 and/or mid-point to a detector for each source is used to provide a common/overlapping sample position. Further, a radial distance for each source/detector combination is set according to absorbance/scattering of the tissue. For instance, the first radial distance, r₁, in the previous example for the first source 401 and the common detector 511 is maintained and used here for the distance between the first source 401 and a first selected detector, 1d,/first selected detection zone to yield a maximum mean photonic path in the dermis 346, as described supra, for a water dominated wavelength, such as about 1410±25 nm. Similarly, the second source 402, third source 403, and fourth source 404 are separated by the second, third, and fourth radial distances of the previous example from a second selected detector, 2 d, a third selected detector, 3 d, and a fourth selected detector, 4 d, respectively, which yields a common mean maximum sample depth, such as in the dermis 346. Combined, a common sample position and common depth system is illustrated as: (1) each source-to-detector distance comprises a mid-point in the probe tip 1400 about a central sampling location/central sampling zone 999, which yields a common location and (2) the radial distances between a given illumination zone-to-detection zone being set with radial distances based upon the wavelength yields a common depth.

Still referring to FIG. 18, the mid-zone 999/sample zone is illustrated on a sample side face of a probe housing of the analyzer 110, such as on a surface of the probe tip 1400. When a linked illumination zone and detection zone reside on opposite sides of the sample zone, a common sampled tissue volume resides in the tissue on the z-axis down from the sample zone, such as if the illumination zone-to-sample zone distance is within ten or twenty percent of the sample zone distance-to-detection zone distance.

Still referring to FIG. 18, selection of a common sample position and common depth is illustrated for a range of skin types/skin states. Through time, a given skin state changes from a thicker dermis to a thinner dermis as a function of time or vise-versa, due to factors such as age, temperature, hydration, and water shifting to the gastro-intestinal region for digestion of recently ingested food. Similarly, the transducer 220 is optionally used to dynamically change the thickness of the dermis 346 as a function of time, such as described supra. Hence, a given illumination zone-to-detection zone distance for a given source/detector combination for a given wavelength range is optionally and preferably dynamically selected based upon the current state of the skin and/or the current state/thickness of the dermis 346. Particularly, for the first illumination zone-to-first detection zone distance, a first set of detectors 1510 includes the first selected detector, 1 d, set at the first radial distance, r₁, from the first illumination zone associated with the first source 401, but also optionally and preferably includes a second optionally selected detection zone positioned radially inward from the first detector and a third optionally selected detection zone positioned radially outward from the first detector, relative to the first illumination zone. As a result, when the dermis 346 is thinner, the radially inwardly positioned detection zone associated with the first set of detectors 1510 is selected/used to sample the dermis and when the dermis 346 is thicker, the radially outwardly positioned detection zone associated with the first set of detectors 1510 is selected/used to sample the dermis. Similarly, the second detector, 2 d, the third detector, 3 d, and the fourth detector, 4 d, of the second set of detectors 1520, a third set of detectors 1530, and a fourth set of detector 1540, respectively, each have radially inward and radially outward positioned detection zones, relative to the second source 402, third source 403, and fourth source 404, respectively, which are optionally dynamically selected as a detected thickness of the dermis 346 changes and/or as a state of the sample changes. As a result of a crossing geometry of the assorted source-to-detector positions, such as illustrated, when a given selected source-to-detector distance is altered, such as to a radially inwardly positioned detection zone, to maintain a constant mean sampling depth, the sample path still crosses the common sample zone. Thus, a common depth and common sampling system is described, where the common sample zone comprises a cross-section length of less than 0.25, 0.5, 0.75, 1, 1.5, 2, 3, or 4 mm.

Tissue Classifier

Referring now to FIG. 19A and FIG. 19B a tissue state classification system 1900 is illustrated. Generally, skin changes with time and spectroscopic signals are used to classify the skin state into two or more groups/classes/states. Calibration models are constructed for each group and when a prediction spectrum is classified into a given group, the corresponding group model is used to predict/estimate a noninvasively determined analyte property. For clarity of presentation and without loss of generality, the following example classifies spectra into three groups based upon a metric determined as a function of illumination zone-to-detection zone distance. More generally, any number of sub-classes are identified using one or more metrics, such an m subclasses and n metrics, where m and n are positive integers, and any number of models corresponding to tissue states are generated as calibration models/applied as predictions from the associated calibration model.

EXAMPLE I

Referring still to FIG. 19A, a first example of use of the tissue state classification system 1900 is illustrated. Initially, a set of data is collected 1910. As illustrated, photons are delivered to a first illumination zone by the first source 401 and photons are collected at a series of detection zones respectively linked to the first detector 511, the second detector 512, and the third detector 513. As illustrated, at a first time, t₁, a best fit to a given metric, such as described supra, is to data from the first detector 511 optically sampling a first mean illumination zone-to-detection zone distance, which corresponds to a first tissue state 1912; at a second time, t₂, the best fit to the given metric is to data from the second detector 512 optically sampling a second mean illumination zone-to-detection zone distance, which corresponds to a second tissue state 1912; and at a third time, t₃, the best fit to the given metric is to data from the third detector 513 optically sampling a third mean illumination zone-to-detection zone distance, which corresponds to a third tissue state 1913. Generally, the metric is applied at a range of radial distances between a given source illuminating at a given illumination zone and a given detector observing a given detection zone. Optionally and preferably, the metric is sensitive to at least a given tissue thickness/optical density, such as described above for a varying thickness of the dermis 346. Optionally and preferably, the metric is alternatively/also sensitive to sample position as even a given layer of the skin, such as the dermis 346, is not optically homogenous. As illustrated, when the metric best fits the first illumination zone-to-first detection zone distance, the data indicates that the sample falls into a first tissue state where a first calibration model /prediction model 1922 is applied, where in a calibration step, the data is optionally added to the calibration model and in a prediction step, the first calibration model is applied to the data. Similarly, when the metric best fits the second tissue state and third tissue state, the data is added to or acted upon by the second calibration/prediction model 1924 and third calibration/prediction model 1926, respectively. Notably, a lack of match of the metric, applied to data, to any tissue state having a corresponding calibration is optionally and preferably used to determine the data as being outlier data. Generally, the classification method is applied to any optical layout described herein.

EXAMPLE II

Referring still to FIG. 19A and referring again to FIG. 19B, the above described tissue classification system 1900 is applied to an overdetermined/multiplexed tissue state classification system 1950. Generally, in the multiplexed tissue state classification system 1950, a tissue state of the person at a point in time or over a short period of time, such as in a period of less than 120, 60, 30, 15, 10, 5, 4, 3, 2, or 1 minutes, is determined more than once, such as with two different wavelength regions, each wavelength region sampled as a function of radial distance to corresponding detector setups. Without loss of generality, two wavelength ranges are illustrated here. However, more generally greater than 2, 3, 4, 5, 7, 10, or 15 wavelength ranges are optionally used, where any given two wavelength ranges comprise at least one of mean wavelengths differing by at least 5, 10, 15, 20, 25, or 50 nm and/or a full-width at half height differing by at least 5, 10, 15, 20, 25, or 50 nm. As illustrated, the second illumination zone 402 optically linked to the second source 402 is separated from a fourth, fifth, and sixth detection zone optically linked to the fourth detector 514, fifth detector 515, and sixth detector 516, respectively. As above, at the first time, t₁, a second metric applied to the collected data 1910 again indicates that the skin is in the first tissue state and that the first calibration/prediction model 1922 is to be updated/used. Similarly, as above, at the second and third times, the second metric identifies the skin as being in the second sample state and third sample state, respectively. Notably, as the first metric and second metric are applied to differing data, in terms of detected wavelengths and radially sampled distances in the skin, which sample overlapping and/or differing tissue depths, the first and second metrics are optionally and preferably combined to determine additional tissue states. For instance, if the first metric is used to identify m tissue states and the second metric is used to identify n tissue states, then the total number of identified tissue states is greater than m and/or n, such as by one or two additional states, and/or is used to identify m+n tissue states. Again, any number of metrics are used and are applied to any number of wavelength ranges where responses to each wavelength ranges are determined at one or more radially separated distances from a corresponding illumination zone.

Common Sample Zone

Referring now to FIG. 20A, FIG. 20B, and FIG. 21, a common zone sampling system 2000 is described. Generally, in the common zone sampling system 2000, an area of the probe tip 1400 of the spectrometer 140 contacting the outer skin surface 330 of the subject during use has a common sample zone 2010. Generally, the common sample zone 2010 is positioned on the z-axis next to the skin, such as above the skin, and sample a common and/or overlapping tissue volume. Particularly, first tissue volumes probed with a first illumination zone-to-detection zone distance overlap second tissue volumes probed with a second illumination zone-to-detection zone distance, which reduces the impact of sample inhomogeneity within a given tissue layer, such as in the epidermis 344 and/or in the dermis 346. Optionally and preferably, the common zone sampling system 2000 also probes a common tissue depth and/or a common sample location as described, supra. For clarity of presentation and without loss of generality, several examples illustrate the common zone sampling system 2000, such as in combination with the common depth system described supra, with a fully or partially multiplexed analyzer, and/or with detectors coupled with two or more sources as a function of time.

EXAMPLE I

Referring still to FIG. 20A, a first example of the common zone sampling system 2000 is described. For clarity of presentation and without loss of generality, this exemplary system is laid out using the first illumination zone-to-detection zone radial system described in previous examples. More particularly, the first illumination zone-to-detection zone is illustrated as two fiber diameters, one intervening “fiber diameter” distance (further described infra), and an inner detector element and an outer detector element are positioned one fiber diameter closer to and further from the illumination source. Similarly, the second, third, and fourth illumination zone-to-detection zone distances from the previous examples is maintained with a separation of 2, 3, and 3.5 fiber diameters between respective illumination zones and detection zone. Similarly, an inwardly positioned detection zone and an outwardly positioned detection zone is provided, coupled to a common zone set of detectors, for each selected illumination zone-to-detection zone distance selected (the 1, 2, 3, and 3.5 fiber diameter spacings). Hence, as the tissue layer thicknesses change, such as with use of the transducer and/or through normal physiological variations with time, sampling of the common tissue layer, such as the dermis 346, is maintained through appropriate selection of the detection element, as described supra. Herein, the fiber diameter optionally and preferably refers to a unit of measure with a corresponding readily manufactured component. Hence a separation referring to a separation of one “fiber diameter” refers to a distance without actually requiring a fiber optic, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 micrometers.

Still referring to FIG. 20A, as illustrated, a common zone set of detectors 1550 is used and a common zone 2010 is an area below the common zone set of detectors 1550 where photons of differing wavelengths sample a common depth and/or a common position, such as by setting illumination zone-to-detection zone distances differently for each wavelength range, further described infra. For instance, when the second source 402 and the second detector position, 2 d, is used, and when the third source 403 and the third detector position, 3 d, is used, each illumination zone-to-detection zone pairing samples: (1) a common depth, as described supra, and (2) a common location, such as any position in common between the two illumination zone-to-detection zone pairings. Similarly, as the tissue state changes and the radially inwardly positioned detection element for the second illumination zone-to-detection zone distance is selected while the radially inwardly positioned detection element for the third illumination zone-to-detection zone distance is selected, a common position, b, is still maintained between the selected second source-detector pairing and the third selected source-detector pairing. Similarly, as the tissue state changes again and the radially outwardly positioned detection element for the second illumination zone-to-detection zone distance is selected while the radially outwardly positioned detection element for the third illumination zone-to-detection zone distance is selected, a common position, 3 d, is still maintained between the selected second source-detector pairing and the third selected source-detector pairing. Generally, for two or more linearly arranged illumination-detection zone pairings, such as for detection zones placed between illumination zones, a common depth and/or a common position exists for the two or more linearly arranged illumination zone pairings even as tissue layer thicknesses change. As illustrated, four linearly arranged illumination-detection zone pairings are illustrated, 1 s-1 d, 2 s-2 d, 3 s-3 d, and 4 s-4 d, where a common zone 2010 comprises: (1) a common maximum mean depth beneath all of the detection positions between the linearly aligned sources and (2) a common sample position exists at or about mid-points between multiple pairs of the linearly aligned sources with detection positions between the paired sources.

Still referring to FIG. 20A, in the common zone sampling system 2000, three or more illumination zone-detection zone pairings sample a common depth and/or a common sample location. For instance, the 1 s-1 d, 2 s-2 d, 3 s-3 d, and 4 s-4 d illumination zone pairings all sample a common depth in the tissue, where the 1 s-2 s-2 d, 3 s-3 d, and 4 s-4 d all sample a common position in the tissue, such as common position b, which is positioned in a common position between each illumination zone-detection zone pairing.

Still referring to FIG. 20A, in the illustrated example of the common zone sampling system 2000, the analyzer 110 is fully multiplexed. Specifically, the first source 401, the second source 402, the third source 403, and the fourth source 404, are all simultaneously operable and detected at corresponding detectors, 1 d, 2 d, 3 d, and 4 d, at the same time while sampling the same tissue depth and overlapping tissue volumes. As the corresponding detectors, 1 d, 2 d, 3 d, and 4 d, each have a radially inwardly positioned detection zone and a radially outwardly positioned detection zone, the common depth and/or the overlapping sampled tissue volumes continue to overlap as the selected illumination zone-to-detection zone varies in correlation with changes in the tissue layer thicknesses.

EXAMPLE II

Referring now to FIG. 20B, a second example of the common zone sampling system 2000 is described where additional “fiber diameter” spacings are used, such as in the optional arc layout 1462 system described supra. For clarity of presentation, the spacings of the illumination and detection zones of the previous example is maintained, while additional detection zones are added. Generally, hardware, such as an optic, drill hole, and/or fiber optic has a diameter and two closely spaced optics, drill holes, and/or fiber optics then have a center-to-center closely packed minimum distance of a diameter of the closely spaced optics, drill holes, and/or fiber optics, such as a distance between a center of the “a” detection zone and the “1d” detection zone, which limits depth resolution in the tissue.

However, following the logic of the optional arc layout 1462, additional optional detection zones, 1 d _(b) and 1 d _(c), are illustrated at intermediate distances between a common illumination zone, 1 s, and: (1) the “a” detection zone and (2) the close packed “1 d” detection zone, such as the illustrated 1⅓ and 1⅔ distances of the 1 d _(b) and 1 d _(c) detection zones, optionally positioned on opposite sides of a common line between illumination zones.

Still referring to FIG. 20B, the set of illumination zones and detection zones positioned on a line is optionally repeated, such as on a second or n^(th) line for use with a second or n^(th) set of wavelength ranges. Further, if the n^(th) line is positioned close to the first line, such as in parallel to the first line and intersecting the 1 d _(b) or 1 d _(c) detection zones, then detectors in the n^(th) line are optionally and preferably used as higher depth resolution detectors for one or more illumination zones in a n+/th or n−/th line parallel and adjacent to the n^(th) line.

EXAMPLE III

Referring now to FIG. 21, a third example of the common zone sampling system 2000 is described where a reduced number of detection zones are used to reduce the size of the probe tip 1400 or the analyzer 110. Particularly, again using the illumination-detection zone spacing of the previous two examples, a single detection zone, c, is used in place of all three of the 1 d, 2 d, 3 d detection zones while maintaining all of the illumination zone-to-detection zone distances of the previous two examples, the tradeoff being a partially multiplexed system as the “c” detector is used as a function of time with use of the first source 401, the second source 402, and the third source 403, respectively.

Referring again to FIG. 20A, FIG. 20B, and FIG. 21, first source-detector combinations having first wavelengths associated with high water absorbance per millimeter of pathlength generally have smaller illumination zone-to-detection zone distances than second source-detector combinations having second wavelength combinations associated with lower water absorbance per millimeter of pathlength. For instance, at a higher water absorbing wavelength, such as at about 1400±50, 1900±50, 2000±50, or 2500±50 nm, a first illumination zone-to-detector distance, associated with detected wavelengths of 1400±50, 1900±50, 2000±50, is less than a second illumination zone-to-detection distance for detection of wavelengths having a medium water absorbance, such as within 10, 20, 30, 40, or 50 nm of a mid-point absorbance of the peak water absorbance bands, such as at 1410, 1520, 1870, 2020, or 2380 nm, and the second illumination zone-to-detection distance used with the medium absorbing wavelengths of water is in turn less than a third illumination zone-to-detection zone distance used for source-detector combinations observing wavelength ranges of light associated with a still smaller water absorbance per millimeter of pathlength, such as within 10, 20, 30, or 40 nm of a first quartile point of the peak water absorbance bands, such as at 1380, 1550, 1850, 2090, or 2350 nm.

Acousto-Optic Analyzer vs. (1) UPI and (2) an AOTF

An applied force-optic analyzer is described herein. Optionally and preferably, the applied force results in a mechanical disturbance of the tissue resulting in a force being applied to the sample. However, in a sub-case of the applied force-optic analyzer, the applied force comprises an acoustic force yielding an acousto-optic analyzer. Notably, in the sub-case of the applied force-optic analyzer being an acousto-optic analyzer, as used herein an acousto-optic analyzer starkly contrasts with both: (1) an ultrasonic photoacoustic imaging (UPI) system and (2) an acousto-optic tunable filter (AOTF) spectrometer, as described infra.

Acousto-Optic Analyzer

As described, an acousto-optic analyzer (AOA) introduces an acoustic vibration wave to the sample to impact the state of the sample, such as tissue, and the state of the sample is measured using an optical probe.

Photoacoustic Imaging

In stark contrast, according to Wikipedia, ultrasonic photoacoustic imaging, also referred to as (UPI), photoacoustic imaging (PI), and/or optoacoustic imaging, delivers non-ionizing laser pulses to biological tissue, which results in absorbed energy and resultant heat in the form of transient thermoelastic expansions detected as wideband megaHertz ultrasonic emissions detected by ultrasonic transducers. The detected signals are used to produce images. As optical absorbance relationships exist with physiological properties, such as hemoglobin concentration and oxygen saturation, the detected pressure waves may be used to determine hemoglobin and oxygen concentration.

Hence, an acousto-optic analyzer starkly contrasts with photoacoustic imaging. Stated again, while the acousto-optic analyzer described herein may induce a heat wave like in photoacoustic imaging, in photoacoustic imaging the sound wave is detected whereas photons, from an external source, are detected in the acousto-optic analyzer described are detected after interacting with the sample being displaced/heated/disturbed by the sound wave.

Acousto-Optic Tunable Filter

According to Wikipedia, an acousto-optic tunable filter (AOTF), diffracts light based on an acoustic frequency. By tuning the frequency of the acoustic wave, the desired wavelength of the optical wave can be diffracted acousto-optically.

Hence, an acousto-optic analyzer (AOA) starkly contrasts with an acousto-optic tunable filter (AOTF) as, while the input sound wave of the AOA may diffract light, the separation of the input light is not the primary use of the sound wave. Indeed, a narrow-band light emitting diode (LED) is optionally used in conjunction with a broadband detector in the acousto-optic analyzer making any separation of the narrow band light source pointless. Further, in the AOA, the sound wave is used to change the state of the biological sample itself, whereas in the AOTF the sound wave is introduced to a birefringent crystal in a wavelength separation module of the spectrometer and is not introduced into the sample.

Still yet another embodiment includes any combination and/or permutation of any of the elements described herein.

The main controller, a localized communication apparatus, and/or a system for communication of information optionally comprises one or more subsystems stored on a client. The client is a computing platform configured to act as a client device or other computing device, such as a computer, personal computer, a digital media device, and/or a personal digital assistant. The client comprises a processor that is optionally coupled to one or more internal or external input device, such as a mouse, a keyboard, a display device, a voice recognition system, a motion recognition system, or the like. The processor is also communicatively coupled to an output device, such as a display screen or data link to display or send data and/or processed information, respectively. In one embodiment, the communication apparatus is the processor. In another embodiment, the communication apparatus is a set of instructions stored in memory that is carried out by the processor.

The client includes a computer-readable storage medium, such as memory. The memory includes, but is not limited to, an electronic, optical, magnetic, or another storage or transmission data storage medium capable of coupling to a processor, such as a processor in communication with a touch-sensitive input device linked to computer-readable instructions. Other examples of suitable media include, for example, a flash drive, a CD-ROM, read only memory (ROM), random access memory (RAM), an application-specific integrated circuit (ASIC), a DVD, magnetic disk, an optical disk, and/or a memory chip. The processor executes a set of computer-executable program code instructions stored in the memory. The instructions may comprise code from any computer-programming language, including, for example, C originally of Bell Laboratories, C++, C#, Visual Basic® (Microsoft, Redmond, Wash.), Matlab® (MathWorks, Natick, Mass.), Java® (Oracle Corporation, Redwood City, Calif.), and JavaScript® (Oracle Corporation, Redwood City, Calif.).

Herein, any number, such as 1, 2, 3, 4, 5, is optionally more than the number, less than the number, or within 1, 2, 5, 10, 20, or 50 percent of the number.

Herein, an element and/or object is optionally manually and/or mechanically moved, such as along a guiding element, with a motor, and/or under control of the main controller.

The particular implementations shown and described are illustrative of the invention and its best mode and are not intended to otherwise limit the scope of the present invention in any way. Indeed, for the sake of brevity, conventional manufacturing, connection, preparation, and other functional aspects of the system may not be described in detail. Furthermore, the connecting lines shown in the various figures are intended to represent exemplary functional relationships and/or physical couplings between the various elements. Many alternative or additional functional relationships or physical connections may be present in a practical system.

In the foregoing description, the invention has been described with reference to specific exemplary embodiments; however, it will be appreciated that various modifications and changes may be made without departing from the scope of the present invention as set forth herein. The description and figures are to be regarded in an illustrative manner, rather than a restrictive one and all such modifications are intended to be included within the scope of the present invention. Accordingly, the scope of the invention should be determined by the generic embodiments described herein and their legal equivalents rather than by merely the specific examples described above. For example, the steps recited in any method or process embodiment may be executed in any order and are not limited to the explicit order presented in the specific examples. Additionally, the components and/or elements recited in any apparatus embodiment may be assembled or otherwise operationally configured in a variety of permutations to produce substantially the same result as the present invention and are accordingly not limited to the specific configuration recited in the specific examples.

Benefits, other advantages and solutions to problems have been described above with regard to particular embodiments; however, any benefit, advantage, solution to problems or any element that may cause any particular benefit, advantage or solution to occur or to become more pronounced are not to be construed as critical, required or essential features or components.

As used herein, the terms “comprises”, “comprising”, or any variation thereof, are intended to reference a non-exclusive inclusion, such that a process, method, article, composition or apparatus that comprises a list of elements does not include only those elements recited, but may also include other elements not expressly listed or inherent to such process, method, article, composition or apparatus. Other combinations and/or modifications of the above-described structures, arrangements, applications, proportions, elements, materials or components used in the practice of the present invention, in addition to those not specifically recited, may be varied or otherwise particularly adapted to specific environments, manufacturing specifications, design parameters or other operating requirements without departing from the general principles of the same.

Although the invention has been described herein with reference to certain preferred embodiments, one skilled in the art will readily appreciate that other applications may be substituted for those set forth herein without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below. 

1. A method for noninvasively determining a state of a person having skin, comprising the steps of: providing an analyzer comprising: a sample probe head comprising a sample side surface; and at least three detection zones along said sample side surface, respectively optically coupled to at least three detector elements, said at least three detection zones positioned on a line passing through a first illumination zone and a second illumination zone, said first illumination zone and said second illumination zone respectively optically coupled to a first source element and a second source element; and detecting, with a common detector element of said set of at least three detector elements, both: (1) first photons comprising a first mean wavelength of emission by said first source; and (2) second photons comprising a second mean wavelength of emission by said second source.
 2. The method of claim 1, further comprising the step of: within a first time period in a period of less than thirty seconds, detecting photons from said first source with each of said at least three detector elements optically coupled to said at least three detection zones on said sample side surface on said line between said first illumination zone and said second illumination zone. wherein a line passes through said first illumination zone, said at least three detection zones, and said second illumination zone.
 3. within a second time period of said period of less than thirty seconds, detecting photons from said second source with each of said at least three detector elements.
 4. The method of claim 3, further comprising the steps of: positioning said first illumination zone on said line at a first radial distance from a longitudinal center point of said at least three detection zones; positioning said second illumination zone on said line at a second radial distance from the longitudinal center point, said second radial distance at least three hundred micrometers longer than said first radial distance; and positioning the set of at least three detection zones between the first illumination zone and the second illumination zone.
 5. The method of claim 4, further comprising the steps of: a first diode emitting the first photons in a range of 1350 to 1480 nm; and a second diode emitting the second photons in a range of 1490 to 1600 nm.
 6. The method of claim 2, further comprising the steps of: a third diode, optically coupled to a third illumination zone on said line, emitting third photons in a range of 1640 to 1800 nm; and within a third time period of said period of less than thirty seconds, detecting photons from said third source with at least two of said at least three detector elements, said third illumination zone positioned at a third radial distance from said center point, said third radial distance at least twenty percent greater than said first radial distance.
 7. The method of claim 1, further comprising the step of: moving a first physical element of said analyzer touching the skin relative to a second physical element of said analyzer touching the skin.
 8. The method of claim 7, said step of moving further comprising the step of: vibrating said first physical element for at least three periods of five to fifty Hertz per period.
 9. The method of claim 7, further comprising the step of: said step of detecting occurring during said step of moving.
 10. The method of claim 7, further comprising the step of: said step of detecting occurring within five minutes of said step of moving.
 11. A method for noninvasively determining a state of a person having skin using a known relative water absorbance as a function of wavelength, comprising the steps of: providing an analyzer comprising: a sample probe head comprising a sample side surface; a first source-detector pair comprising a first radial distance between an associated first illumination zone-to-first detection zone distance along said sample side surface; and a second source-detector pair comprising a second radial distance between an associated second illumination zone-to-second detection zone distance along said sample side surface; said first source-detector pair detecting a first mean wavelength diffusely transmitting through the skin at said first radial distance; said second source-detector pair detecting a second mean wavelength diffusely transmitting through the skin at said second radial distance, wherein a line passes through said first illumination zone, said first detection zone, said second detection zone, and said second illumination zone, wherein the first mean wavelength comprises a provided standard water absorbance per millimeter of pathlength, wherein the second mean wavelength comprises a second provided standard water absorbance per millimeter of pathlength less than seventy-five percent of the first provided standard water absorbance, said second radial distance at least twenty percent larger than said first radial distance.
 12. The method of claim 11, further comprising the steps of: providing at least three detection zones along said sample side surface, respectively optically coupled to at least three detector elements, said at least three detection zones positioned on the line between said first illumination zone and said second illumination zone; and detecting, with a common detector element of said set of at least three detector elements, both: (1) first photons in said step of detecting the first mean wavelength and (2) second photons in said step of detecting the second mean wavelength.
 13. The method of claim 11, further comprising the step of: over a first time period, simultaneously detecting photons from a first source of said first source-detector pair with each of at least three detector elements optically coupled to at least three detection zones on said sample side surface on said line between said first illumination zone and said second illumination zone.
 14. The method of claim 13, further comprising the step of: over a second period of time, within one-half second of said first period of time, simultaneously detecting photons from a second source of said second source-detector pair with each of said at least three detector elements optically coupled to said least three detection zones on said sample side surface on said line between said first illumination zone and said second illumination zone.
 15. The method of claim 14, further comprising the steps of: said first source, comprising a first diode, emitting light in a first wavelength range of at least one of 1350 to 1450 nm and 1850 to 1950 nm; and said second source, comprising a second diode, emitting light in a second wavelength range of 1490 to 1600 nm.
 16. The method of claim 15, further comprising the step of: over a third period of time, within one second of said first period of time, simultaneously detecting photons from a third source with at least two of said at least three detector elements optically coupled to said at least three detection zones on said sample side surface on said line between said first illumination zone and said second illumination zone.
 17. The method of claim 16, further comprising the step of: said third source illuminating a third illumination zone, on the line, positioned radially outward from a center of a common detector element of said at least three detector elements relative to said second illumination zone, said third source comprising a diode emitting light in a range of 1650 to 1800 nm.
 18. The method of claim 11, further comprising the step of: transmitting data from said analyzer to a personal communication device of said person.
 19. A method for noninvasively determining a state of a person having skin, comprising the steps of: providing an analyzer comprising: a sample probe head comprising a sample side surface; a first source-detector pair comprising a first radial distance between an associated first illumination zone-to-first detection zone distance along said sample side surface; and a second source-detector pair comprising a second radial distance between an associated second illumination zone-to-second detection zone distance along said sample side surface; said first source-detector pair detecting a first mean wavelength diffusely transmitting through the skin at said first radial distance; said second source-detector pair detecting a second mean wavelength diffusely transmitting through the skin at said second radial distance, wherein a line passes through said first illumination zone, said first detection zone, said second detection zone, and said second illumination zone, wherein the first mean wavelength comprises a first absorbance-to-first radial distance ratio at least ten percent greater than a second absorbance-to-second radial distance ratio of the second mean wavelength, said second radial distance at least twenty percent greater than said first radial distance, the first mean wavelength and the second mean wavelength differing by at least twenty-five nanometers.
 20. The method of claim 19, further comprising the step of: moving a first physical element, of said analyzer, touching the skin relative to a second physical element, of said analyzer, touching the skin. 